Clinical ReviewIncidence of narcolepsy after H1N1 influenza and vaccinations: Systematic review and meta-analysis
Introduction
Narcolepsy is a complex chronic hypersomnia syndrome affecting approximately 20–50 per 100,000 persons [1], [2], [3], [4]. The previously reported estimated incidence is approximately 1 per 100,000 persons per year with the peak of onset at the 2nd decade [4], [5], [6]. Two distinct disease categories can be distinguished. Narcolepsy type 1 (NT1) is likely caused by an autoimmune-mediated destruction of hypocretin-producing neurons in the lateral hypothalamus [7], [8]. NT1 is almost always associated with cataplexy. In narcolepsy type 2 (NT2), there is no hypocretin deficiency or cataplexy.
An increased incidence of narcolepsy was observed in six European countries after the pandemic influenza A virus, A(H1N1)pdm09 (“swine flu”), vaccination campaign during the winter 2009–2010. The first signal was observed in Finland and Sweden, followed by France, England, Ireland, and Norway – all the countries where AS03-adjuvanted pandemic vaccine Pandemrix (GlaxoSmithKline Biologicals, Wavre, Belgium) was widely used ∗[9], ∗[10], ∗[11], ∗[12], ∗[13], ∗[14], [15]. In the European Union and European Economic Area (EU/EEA), three centrally and five nationally authorized vaccines were used with coverage of at least 46.2 million people [15]. Five vaccines had no adjuvant, two had MF59-adjuvant and one, Pandemrix, had AS03 adjuvant. Pandemrix was the most used vaccine (over 30.5 million people vaccinated) in Europe. In the United States, over 90 million doses of pandemic H1N1 vaccination were administered in 2009–2010, but no adjuvanted vaccines were used [16].
One particular problem with the observational studies is their proneness to various biases such as confounding by natural H1N1 infection, and ascertainment, recall and selection biases. For instance, a seasonal and temporary increase in the incidence of narcolepsy was also seen in China after the 2009–2010 pandemic influenza A virus without clear relation to any vaccine [17], [18], [19]. This implicates the possibility that the H1N1 virus per se could be a triggering factor for the development of narcolepsy at least in Asian population. Furthermore, it was recently reported that influenza virus is capable of damaging hypocretinergic neurons in immune-depleted mice causing a narcolepsy-resembling phenotype [20].
Narcolepsy has also been a rare, underdiagnosed disease with long delay between onset of symptoms and diagnosis [21]. Therefore, the recognition of the syndrome may have been limited especially among primary health care practitioners before increased media attention after H1N1-related cases. Simply an increase in attention towards this disease could lead to increase in the number of diagnosed cases without an actual rise in incidence. The methods in the observational studies are also somewhat heterogeneous. For example, incorrect case confirmation and inaccurate gathering of information on the symptom onset and vaccination date could cause ascertainment bias [22].
Even if observational studies could prove strong connection between vaccination and narcolepsy, the true causative relationship requires a pathogenic-proven link. However, specific biological mechanisms behind the vaccine-associated narcolepsy are still incompletely understood [8]. Some evidence exists on increased immune response against viral nucleoprotein in Pandemrix in subjects who have genetic predisposition to narcolepsy by HLA DQB1*06:02 allele [23].
Taken into account biological and epidemiological controversies in connection between narcolepsy, H1N1 influenza virus infections and vaccinations, we conducted a systematic review and meta-analysis to clarify the risk of narcolepsy associated with H1N1 vaccines and infections.
Section snippets
Literature search and selection criteria
We searched PubMed, Web of Science, and Scopus for all articles reporting incidence and risk of Pandemrix H1N1-vaccination-associated narcolepsy in November 2016 without a language restriction. The full search string was (narcolepsy[MeSH] or narcolepsy) AND (vaccines[MeSH] OR vaccination[MeSH] OR influenza[MeSH] or Pandemrix OR vaccines OR vaccination).
We also checked the references of all relevant studies and review articles to identify additional sources. Webpages of National Institute for
Included studies
Literature search resulted in 310 articles (Fig. 1) after removal of duplicate papers. Additional ten articles were included outside of the search as explained in the methods section ∗[12], [15], [25], [26], [27], [28], [29], [30], ∗[31], [32]. Seventy-five reviews were excluded, but their reference lists were examined to include any appropriate articles not retrieved in the literature search. After screening for the titles and abstracts, full texts of 78 articles were read. Forty-nine studies
Discussion
In this meta-analysis we found a 5- to 14-fold increase in incidence of narcolepsy in children and adolescents and a 3- to 7-fold increase in adults in the countries where Pandemrix vaccine was widely used in 2009–2010 (Finland, France, Ireland, the Netherlands, Norway, Sweden and the UK). The risk in the observational studies is dependent on the used index date. Use of onset of symptoms as index date produced the highest risk followed by date of healthcare contact, referral to sleep studies,
Conflicts of interest
Dr. Dauvilliers reports personal fees from UCB, Bioprojet, Jazz, Theranexus, and Actelion, outside of the submitted work. Dr. Partinen reports grants from Academy of Finland and personal fees from UCB, GSK, Leiras-Pharma, MSD, and Orion, outside of the submitted work. Dr. Alakuijala reports no disclosures.
Acknowledgements
We thank Eric Burns for language editing. Dr. Sarkanen reports grants from the Finnish Medical Foundation during conduct of the study.
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